Using computer simulations to investigate the molecular
mechanisms that cause cell death in Alzheimer's patients

Principal Investigators

Background

The current lack of understanding about the molecular origins of Alzheimer's Disease (AD) greatly limits our ability to
rationally design AD therapies. Although the ultimate elucidation of these molecular mechanisms will require the combined
efforts of neurologists, molecular biologists and others in the field of AD research, we are addressing the challenge with
all-atom computational modeling of particular protein-cell interactions that are thought to be responsible for neuronal cell
death in AD patients. Knowledge gained through these simulations about the nature of these interactions could provide
important clues that will help researchers design effective AD treatments.

Interactions of Aβ peptides with cellular membranes

Small Aβ peptides have been identified as apparent agents of AD, causing death of neuron cells over the course of disease
progression. Specifically, it is believed that, when Aβ peptides associate with each other and form aggregates, they become
cytotoxic to cells.

However, it is not known why Aβ aggregates are cytotoxic. Is it because they interact with cellular membranes,
disordering them and causing uncontrollable flow of ions, which in turn leads to cell death? Or does the same outcome result
from Aβ aggregates forming structured channels in the membrane?

In our recent study, published in the Journal of Physical
Chemistry, we analyzed how individual Aβ peptides bind and penetrate a model lipid bilayer, which serves as a
less complex and more computationally approachable proxy for a cellular membrane. We showed that upon binding the peptide
undergoes dramatic structural transition, forming a helical structure, and we explained this observation based on Aβ
sequence properties.

With the simulations being supported by the CAAD project, we are studying aggregation of Aβ peptides
mediated by cellular membranes, with the goal of answering the questions posed above. These efforts are partially supported
by NIH, specifically, the National Institute of Aging, through the grant awarded to George Mason University and Parabon
Computation.

Implications for other disorders

Research into Aβ peptides, although most prominently focused on Alzheimer's disease, also has implications for other
related syndromes, such as mild cognitive impairment. Furthermore, traumatic brain injury due to sports or other activities
has also been linked to Aβ loads in affected brains.
Therefore, understanding the cytotoxic mechanisms of Aβ will not only have a lasting impact on Alzheimer's research,
but can help resolve related issues in other indications as well.